This application is for a Medication Development Unit (MDU) which will complement our existing program of research in finding effective treatments for drug addiction. The tight integration of this MDU within the general umbrella of the Penn/VA Center for Studies of Addiction, allows us to propose a substantial amount of research (two large scale clinical trials, a laboratory study, and pilot projects) with minimal new resources. Specifically, the theme of this center focuses on the use of innovative strategies to find effective pharrnacotherapies to treat cocaine dependence. The core facilities Include a data management unit, significant computer support including a wide area network to facilitate Center communication, human labs, and a urine testing lab. This Center proposal includes a core and three projects plus a series of pilot studies on GABAergic agents. The core will have general administrative functions and help with the overall scientific direction, data management, common clinical services, subject recruitment, pharmacy services, laboratory functions, and coordination of the individual projects. In addition, the core will conduct pilot studies of promising pharmacological agents for cocaine dependence related to enhancing GABAergic activity, creating new directions for clinical trials. Project l investigates the use of amantadine and propranolol, alone or in combination, in subjects in the early stages of their recovery who have recently had a positive urine for cocaine and a high score on the Cocaine Selective Severity Assessment. Our preliminary data suggest that pharmacotherapy is particularly helpful for this subgroup of patients. Project 2 will test the use of naltrexone and disulfiram, alone and in combination, in the treatment of cocaine dependence complicated by alcohol dependence. This study attempts to replicate and extend recent findings that disulfiram reduces both cocaine and alcohol use in cocaine- alcohol dependent patients. In addition, it extends our earlier pilot study of naltrexone on alcohol abusing cocaine dependent subjects. The combination of these two compounds may be particularly helpful in enhancing treatment retention and reducing cocaine and alcohol use. Project 3 evaluates the effects of various medications on cue reactivity and the predictive validity of cue reactivity on clinical outcome. By taking subjects randomized from Project 1, 2 and the core pilot projects, subjects will be administered cue screening prior to receiving study medications, and again about 4 weeks into the clinical trial while on study medications. In addition to testing specific medications, the Center will utilize an integrated series of projects to improve our understanding of cocaine treatment as it relates to stabilization and detoxification as treatment goals versus reducing the number and intensity of cocaine relapses. In addition we will investigate the use of cue reactivity as it predicts treatment outcome and as a possible screening tool for new medications.